Synthesis of Stable and Potent δ/μ Opioid Peptides:  Analogues of H-Tyr-c[d-Cys-Gly-Phe-d-Cys]-OH by Ring-Closing Metathesis

Abstract

Ring-closing metathesis has emerged as a powerful tool in organic synthesis for generating cyclic structures via C-C double bond formation. Recently, it has been successfully used in peptide chemistry for obtaining cyclic molecules bridged through an olefin unit in place of the usual disulfide bond. Here, we describe this approach for obtaining cyclic olefin bridged analogues of H-Tyr-c[DCys-Gly-Phe-Cys]-OH. The synthesis of the new ligands was performed using the second generation Grubbs' catalyst. The resulting cis-8 (cDADAE) and trans-9 (tDADAE) were fully characterized and tested at δ, μ, and κ opioid receptors. Also the linear precursor 13 (lDADAE) and the hydrogenated derivative 11 (rDADAE) also were tested. All the cyclic products containing a olefinic bond are slightly selective but highly active and potent for the δ and μ opioid receptors. Activity toward the κ opioid receptors was absent or very low.

Peptidomimetics, a synthetic tool of drug discovery

“…In addition, they may be closer mimetics of a natural β-turn with some flexibility which may be important for the effective interactions between a mimetic and a target protein, especially in the induced fit scenario. For example, analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH in which the disulfide bridge is replaced with a dicarba bridge retained high biologically activities [28].…”

“…Indolizidine-2-one and -9-one amino acids, representing 6,5 and 5,6 scaffolds, were used as β-turn scans to explore the conformational requirements for activity of analogues of Calcitonin-gene related peptide (CGRP) antagonist, together with aza-aminoacid scans [32]. The importance of a type II' β-turn centered at Gly 33 [27][28][29][30][31][32][33][34][35][36][37] has been illustrated by increased antagonistic potency of the azaGly 33 and indolizidine-2-one amino acid [33][34] analogues. In addition, the improved metabolic stability and longer duration of action qualifies those scans to be another peptidomimetic research tool.…”

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

“…Other examples of hydrocarbon bridges as isosteric replacements of disulfides in bioactive peptides have been reviewed [4,6] and reported in the literature, among others, to arrive at redox-stable analogs of sunflower trypsin inhibitors [88], cyclic dermorphin tetrapeptides [89], cyclic enkephalin peptides [90,91], octreotide- [92][93][94] and somatostatin-derived peptides [95], and an antimicrobial human β-defensin-1 derivative [96] and leucocin A analogs [97].…”

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

“…The saturated product (40c) is 10-fold less potent. 102 The mono-sulfide-bridged lanthionine enkephalin analogs 41-44 ( Figure 8.14, Table 8.4) were described by Goodman and coworkers. 101,103 The functional in vitro activity of the compounds was found to parallel the binding affinities.…”